A. Field of the Invention
The present invention relates generally to the fields of oncology, obstetrics, and gynecology. More particularly, it concerns diagnosing people at risk for developing uterine diseases, uterine conditions or pre-term labor. This invention further concerns methods of treating and preventing uterine diseases or conditions, ovarian diseases or conditions, and pre-term labor.
B. Description of Related Art
Preterm labor and uterine diseases and conditions pose serious health concerns in today's society. A number of women are subject to preterm labor that results in pregnancy complications affecting an estimated 8 to 10 percent of births in the United States each year (Weismiller, 1999). Moreover, it is estimated that 25-50% of all women are diagnosed with a uterine disease or condition in their lifetime.
1. Preterm Labor
Preterm labor refers to true labor occurring before the end of the 36th week of pregnancy and it is characterized by cervical effacement, dilatation and increased uterine irritability (Weismiller, 1999). Studies have shown that women with a history of previous preterm delivery are at a greater risk of recurrence (Weismiller, 1999).
Strategies to prevent preterm labor have focused on early diagnosis and on clinical markers (Weismiller, 1999). An example of some of the clinical markers have included monitoring cervical change, uterine contractions, bleeding and changes in fetal behavioral states (Weismiller, 1999). Despite evaluation of such markers, women continue to undergo preterm labor with and without symptoms. The underlying mechanisms underlying preterm labor have yet to be elucidated and understood.
In fact, to date there has been no genetic information regarding women at risk for preterm labor, nor has there been any data involving specific polymorphisms that can arise in the COMT polypeptide and the likelihood of a woman developing preterm labor. Therefore, there is a need for better prognostic and diagnostic tests for women at risk for preterm labor, particularly a genetic-based test. Such a test can then be used to identify women at risk for preterm labor and increase the likelihood of successful treatment.
Current treatments for the prevention and treatment of preterm labor include the administration of an antibiotic, a tocolytic drug, a non-estradiol anti-inflammatory drug or a calcium channel blocker. Nonetheless, many women undergo preterm labor even if such treatments are administered. Consequently, there continues to be a need for improved therapeutic options for the treatment of preterm labor.
2. Uterine Diseases and Conditions
A uterine disease or condition can be characterized by a number of disorders ranging from adenomyosis, endometriosis, endometrial hyperplasia, leiomyosarcoma, benign tumor, malignant tumor, dysfunctional uterine bleeding, endometrial cancer, premenstrual syndrome or abnormal uterine bleeding. Known risk factors for developing a uterine disease such as uterine cancer, for example, include prolonged estrogen exposure, early menarche, late menopause, no children, failure to ovulate and obesity. Suggested prevention measures for people determined to be at risk for developing a uterine cancer have been identified as including maintaining an ideal weight, annual pelvic exams and endometrial biopsy at menopause.
Leiomyomas (fibroids) are benign smooth-muscle cell (SMC) tumors of the uterus and are the most common pelvic tumors in women. These tumors occur primarily during the reproductive years and are the most common indication for hysterectomy in women. Unfortunately, alternative therapies are few and hysterectomy or myomectomy being the treatment of choice in most cases (Martel et al., 2004). The discovery and development of medicinal therapies for uterine leiomyoma have been hampered by a lack of understanding regarding the etiology and molecular mechanisms underlying the development of these lesions. Although the precise pathophysiology of fibroids is unknown, several endogenous or environmental factors that modulate risk for developing uterine leiomyoma affirm the hormone responsive nature of this disease. Early Menarche, African-American ethnicity, nulliparity, and obesity are among the common risk factors for Leiomyomas. The impact of many of these factors has often been attributed to their effects upon estrogen and progesterone levels or metabolism that may in part reflect aspects of a woman's hormonal milieu (Gordon et al., 2003). Furthermore, another potential mechanism for development of leiomyomas is a decrease in apoptosis. Matsuo et al. (1997) found that Bcl-2 protein, an apoptosis-inhibiting gene product, was abundantly expressed in leiomyomata relative to that in normal myometrium.
In some studies, it was suggested that a specific COMT polymorphism at position 108 of the COMT polypeptide (Val108→Met108) appears to be associated with an increased risk of breast cancer and Parkinson's disease in humans. (Zhu, 2002; Lavigne et al., 1997; Thompson et al., 1998; Huang et al., 1999; Yim et al.; 2001; Xie et al.; 1999; Mitrunen et al.; 2001 and Goodman et al, 2001). Another study examined the relationship between the COMT polymorphism (Val158→Met158) and the development of anorexia nervosa in patients. (Frisch et al., 2001; Zhu 2002). However, no such information has been suggested with respect to uterine diseases or conditions.
One study that used enzyme activity to predict subject phenotype (McLeod et al., 1994) observed no gender difference in COMT enzymatic activity. Due to high prevalence of uterine leiomyomas (77% in autopsy studies) (Cramer and Patel, 1990), and relatively young age of women in McLeod et al. (1994) (34-36 years), it was apparent that several of the volunteer subjects were harboring either non-symptomatic or pre-symptomatic uterine leiomyomas.
Developments of therapeutic agents which are capable of reversing the tumor growth in Leiomyomas without the unwanted side effects are urgently needed for the conservative treatment of Leiomyomas. Pharmacological agents that modulate the hormonal milieu and target the growth factors and apoptotic/antiapoptotic could be a useful treatment for Leiomyomas. It has been suggested that there is a similarities between the biology of leiomyomas and other SMCs disease such as atherosclerosis (Nowak, 2001).
2-Methoxyestradiol (2-MeO-E2) is a nonpolar endogenous E2 metabolite formed by the COMT-mediated O-methylation of 2-hydroxyestradiol, a major catechol E2 metabolite formed in humans (Zhu and Conney 1998a,b). Recent study suggested that 2-Methoxyestradiol inhibited DNA synthesis, cell numbers, and collagen synthesis in SMCs (Zacharia et al., 2003). 2-Methoxyestradiol binds at the colchicine-binding site of tubulin and disrupts tubulin polymerization, a process essential for cell division. Also, 2-methoxyestradiol blocks SMC growth in both G0/G1 and G2/M phases of the cell cycle, by inhibiting cyclin-D1 and cyclin-B1 expression (Barchiesi et al., 2003). Moreover, 2-methoxyestradiol inhibits phosphorylation of retinoblastoma protein, ERK1/2 (MAPK) (Dubey et al., 2000) and upregulates Cdk inhibitor p27 (Barchiesi et al., 2003). Because 2-methoxyestradiol has a low systematic toxicity, considerable research efforts have been initiated lately to explore the usefulness of 2-MeO-E2 as a low-toxicity chemotherapeutic agent for human breast cancer as well as for other cancers. Currently, larger-scale clinical trials are underway to evaluate the effectiveness of 2-MeO-E2 as an antitumor agent in prostate and breast cancer.
However, to date, there has been evidence that such treatments can be used for genitourinary conditions or diseases. Nor have there been any studies suggesting a correlation between specific polymorphisms that can arise in the COMT polypeptide and the likelihood of developing a genitourinary disease or condition, such as a uterine cancer. Furthermore, while some treatment for genitourinary conditions—such as uterine diseases and conditions—exist, women continue to suffer from these diseases and conditions. Thus, diagnostic tests are needed to identify women at risk for developing a genitourinary condition or disease, and improved treatment options are similarly desirable.